Prostate cancer (PCA) is the second leading cause of cancer-related deaths in the United States. Androgen ablation is often used as therapy because it stimulates apoptosis in androgen-dependent prostate cancer cells. PCA cells are often androgen-independent, and some become androgen-independent over time. Androgen-independent cells are eventually selected during androgen ablation therapy and progression to an androgen-independent state is the primary cause of mortality in men with prostate cancer. Androgen-independent tumor cells are more difficult to destroy, having been shown to be insensitive to many anti-cancer drugs and tumor necrosis factor-alpha (TNF-alpha) therapy. Androgen-independent PCA cells are responsive to high doses of chemotherapeutic drugs such as cisplatin and etoposide, but the drugs themselves have an undesirable level of systemic toxicity. Providing levels high enough to affect a significant number of tumor cells may pose an unacceptable risk to the patient.
Androgen-independent prostate cancer cells (e.g., PC-3 and DU145) have proven to be TNF-α insensitive, whereas androgen-sensitive prostate cancer cells (e.g., LNCaP) are TNF-α sensitive. Resistance to the pro-apoptotic effects of TNF-α and many known chemotherapeutic agents has been associated with constitutive activation of NF-kB in many cancer cells. Muenchen, et al., (Clin. Cancer Res. 2000, 6: 1969-1977) demonstrated that inhibition of NF-kB with the IκBα “super-repressor” (p6R-I κBS32A+S36A) could sensitize previously insensitive prostate cancer cells to the effects of TNF-α. In most cell types, NF-kB is constitutively present in the cytosol in a latent, inactive form where it is retained through interaction with IkB proteins, which bind to NF-kB and mask its nuclear localization sequence (NLS). In some cell types, NF-kB is constitutively activated. Activation of NF-kB in the cell involves ubiquitination of IkB so that it is degraded by the 26S proteasome. Removal of IkB exposes the NLS and results in translocation of NF-kB to the nucleus, where it acts to protect the cell from apoptosis.
Constitutive activation of NF-kB has been reported in a variety of tissues, including, for example, breast, pancreas, liver, bladder, lung, kidney, and ovary. Neuroblastoma, Hodgkin's lymphoma, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, Burkitt's lymphoma, and multiple myeloma are among the cancers associated with constitutive activation of NF-kB. Inhibition of NF-kB nuclear translocation has also been demonstrated to have some effect in sensitizing multiple myeloma to the pro-apoptotic effects of doxorubicin (Mitsiades, et al., Blood, (June 2002) 99: 4079-4086). NF-kB activation has therefore become a target for improving cancer therapy.
It is preferable to utilize target-specific agents for cancer therapy and to develop agents that increase the destruction of cancer cells without similarly affecting normal cells. What are especially needed are new agents for those cancers that have shown resistance to current modes of therapy and therefore have an increased mortality rate.